POLR3B – Hypomyelinating Leukodystrophy 8

Biallelic pathogenic variants in POLR3B cause autosomal recessive hypomyelinating leukodystrophy 8 (HLD8) characterized by deficient cerebral myelin formation, cerebellar atrophy, hypodontia and hypogonadotropic hypogonadism. POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, essential for transcription of tRNAs and other small noncoding RNAs.

Initial genetic evidence came from whole-exome sequencing of three unrelated individuals with HLD8 features, identifying compound heterozygous POLR3B variants in two probands: a nonsense variant c.1648C>T (p.Arg550Ter), a splice‐site variant c.1857-2A>C, and two missense variants c.2303G>A (p.Arg768His) and c.2778C>G (p.Asp926Glu) (PMID:22036171). More recently, a family with two affected siblings was described carrying c.165_167del (p.Ile55_Lys56delinsMet) and c.1615G>T (p.Val539Phe) in trans, segregating with cerebellar atrophy, intellectual disability, hypogonadotropic hypogonadism and visual loss (PMID:36650939).

To date, at least 4 missense, 1 nonsense, 1 splice‐site and 1 in‐frame deletion variants have been reported across 4 probands with confirmed autosomal recessive inheritance. There are no recurrent or founder alleles noted, and carrier frequency remains very low in population databases.

Functional studies demonstrate loss‐of‐function as the pathogenic mechanism. In patient fibroblasts, c.165_167del and c.1615G>T transcripts and proteins are sharply reduced by qPCR and western blot, and zebrafish lacking human POLR3B orthologs recapitulate central hypomyelination (PMID:36650939). In oligodendroglial precursor cells, the R550X mutation causes POLR3B aggregation in lysosomes, reduced mTOR signaling and impaired morphological differentiation, reversible with ibuprofen (PMID:35225888). A conditional Polr3bΔ10 mouse model exhibits severe hypomyelination, hypodontia, hypogonadism and cerebellar atrophy by postnatal induction (PMID:37635302).

No conflicting evidence disputing the POLR3B–HLD8 association has been reported. Together, genetic and experimental data provide strong support for POLR3B haploinsufficiency as the driver of HLD8, meeting ClinGen criteria for a strong gene–disease association.

Key Take-home: POLR3B should be included in autosomal recessive leukodystrophy gene panels to facilitate molecular diagnosis and genetic counseling.

References

• American Journal of Human Genetics • 2011 • Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. PMID:22036171
• Clinical Genetics • 2023 • Identification of POLR3B biallelic mutations-associated hypomyelinating leukodystrophy-8 in two siblings. PMID:36650939
• Neurology International • 2022 • Hypomyelinating Leukodystrophy 8 (HLD8)-Associated Mutation of POLR3B Leads to Defective Oligodendroglial Morphological Differentiation Whose Effect Is Reversed by Ibuprofen. PMID:35225888
• Brain: a Journal of Neurology • 2023 • Hypomyelination, hypodontia and craniofacial abnormalities in a Polr3b mouse model of leukodystrophy. PMID:37635302

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